Alkenyl and alkinylureido cephalosporins

ABSTRACT

Alkenyl and alkinylureido cephalosporins of the formula ##STR1## wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, trihaloethyl, a salt forming ion, or the group ##STR2## R 1  is hydrogen or methoxy; R 2  is lower alkenyl or lower alkinyl, R 3  is hydrogen or lower alkyl; R 4  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl, substituted phenyl, substituted phenyl-lower alkyl, or certain heterocyclic groups; R 5  is hydrogen or lower alkyl; R 6  is lower alkyl; and X is hydrogen, lower alkanoyloxy, ##STR3## or certain heterothio groups; are disclosed. These compounds are useful as antibacterial agents.

BACKGROUND OF THE INVENTION

Cephalosporins having a ureido acyl side chain are disclosed in U.S.Pat. Nos. 3,673,183; 3,708,479; 3,833,568; and 3,860,591. Cephalosporinshaving various acyl side chains and a 7α-methoxy substituent are taughtin various U.S. patents including U.S. Pat. Nos. 3,775,410; 3,780,031;3,780,033; 3,780,034; 3,780,037; 3,843,641; etc.

Cephalosporins having an acylureido acyl side chain are disclosed inU.S. Pat. Nos. 3,687,949 and 3,925,368 and German OffenlegungsschriftNos. 2,513,954 and 2,514,019.

SUMMARY OF THE INVENTION

This invention relates to new alkenyl and alkinylureido- 7α-methoxy ordesmethoxy cephalosporin derivatives of the formula ##STR4## Rrepresents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-loweralkyl, tri(lower alkyl) silyl, trihaloethyl, a salt forming ion, or thegroup ##STR5## wherein R₅ is hydrogen or lower alkyl and R₆ is loweralkyl. R₁ represents hydrogen or methoxy. The R₁ substituent is in theα-configuration as indicated by the broken lines (.tbd.).

R₂ represents lower alkenyl or lower alkinyl.

R₃ represents hydrogen or lower alkyl.

R₄ represents hydrogen, lower alkyl, cycloalkyl, cycloalkenyl,cycloalkadienyl, phenyl, phenyl-lower alkyl, substituted phenyl,substituted phenyl-lower alkyl, or certain heterocyclic groups.

X represents hydrogen, lower alkanoyloxy, certain heterothio groups,##STR6##

When X is pyridinium or carbamoyl substituted pyridinium, the compoundscan be structurally represented as having the formula ##STR7## wherein Zis hydrogen or carbamoyl.

DETAILED DESCRIPTION OF THE INVENTION

The various groups represented by the symbols have the meaning definedbelow and these definitions are retained throughout this specification.

The lower alkyl groups referred to throughout this specification includestraignt or branched chain hydrocarbon groups containing 1 to 8 carbonatoms, preferably 1 to 4 carbons. Examples of the type of groupscontemplated are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.The lower alkoxy groups include such lower alkyl groups attached to anoxygen, e.g., methoxy, ethoxy, propoxy, etc. The phenyl-lower alkyl anddiphenyl-lower alkyl groups include such lower alkyl groups attached toa phenyl, preferably benzyl, phenethyl, and diphenylmethyl.

The lower alkenyl and lower alkinyl groups referred to throughout thisspecification include straight or branched chain hydrocarbon groupscontaining 2 to 8 carbon atoms and one double or triple bond, preferably2 to 4 carbons. Examples of the types of group contemplated are --CH₂--CH=CH₂, --CH=CH₂, --CH₂ --CH=CH--CH₃, ##STR8## --CH₂ --C.tbd.CH, --CH₂--C.tbd.C--CH₃, etc.

Cycloalkyl refers to groups having 3 to 7 carbons in the ring, i.e.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Theterm cycloalkenyl also represent rings having 3 to 7 carbons with onedouble bond, i.e. cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. Theterm cycloalkadienyl represents a ring having 6 or 7 carbons with twodouble bonds located at various positions such as 1,4-cyclohexadienylwhich is preferred.

The substituted phenyl and substituted phenyl-lower alkyl groups includeone or two substituents selected from halogen (preferably chlorine orbromine), lower alkyl of 1 to 4 carbons (preferably methyl or ethyl),lower alkoxy of 1 to 4 carbons (preferably methoxy or ethoxy), andhydroxy, e.g. 2-, 3-, or 4-chlorophenyl, 2-, 3-, or 4-bromobenzyl, 2-,3-, or 4-hydroxyphenyl, 3,5-dichlorophenyl, 2-, 3-, or 4-methylphenyl,2-, 3-, or 4-ethoxyphenyl, etc.

The salt forming ions represented by R may be metal ions, e.g.,aluminum, alkali metal ions such as sodium or potassium, alkaline earthmetal ions such as calcium or magnesium, or an amine salt ion, of whicha number are known for this purpose, for example, phenyl-loweralkylamines such as dibenzylamine, N,N-dibenzylethylenediamine, loweralkylamines such as methylamine, triethylamine, and N-loweralkylpiperidines such as N-ethylpiperidine. Sodium and potassium are thepreferred salt forming ions.

The halogens are the four common halogens, of which chlorine and bromineare preferred. In the case of the trihaloethyl group represented byR,2,2,2-trichloroethyl is preferred.

Trimethylsilyl is the preferred tri(lower alkyl) silyl group.

The heterocyclic groups represented by R₄ are 2-thienyl, 3-thienyl,2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. Also includedwithin the meaning of R₄ are such heterocyclics having a halogen(preferably Cl or Br) or a lower alkyl of 1-4 carbons (preferably methylor ethyl) substituent, i.e. 2-(4-chlorothienly), 3-(4-methylthienyl),etc.

Lower alkanoyloxy refers to a group of the formula ##STR9## whereinlower alkyl is of 1 to 4 carbons, preferably wherein lower alkyl ismethyl.

The heterothio groups represented by X are ##STR10## wherein R₇ ishydrogen or lower alkyl of 1 to 4 carbons (preferably methyl or ethyl)and R₈ is hydrogen, lower alkyl of 1 to 4 carbons (preferably methyl orethyl), methoxy, hydroxy, or halogen (preferably chlorine).

The desmethoxy compounds of formula I (R₁ is hydrogen) can be preparedby several methods. For example, an α-amino intermediate of the formula##STR11## wherein X is hydrogen, lower alkanoyloxy, or heterothio can bereacted, preferably in the form of its trifluoroacetic acid salt, with acompound of the formula

    R.sub.2 --N=C=O                                            (III) ##STR12## wherein R.sub.2 and R.sub.3 are as defined above and halo is Cl or Br to yield the compound of formula I wherein R.sub.1 is hydrogen and X is hydrogen, lower alkanoyloxy, or heterothio.

The α-amino intermediate of formula II can be prepared by variousmethods such as by acylating a 7-amino cephalosporin of the formula##STR13## with a substituted α-amino acid of the formula ##STR14##wherein Y is a protecting group such as ##STR15## The α-amino protectinggroup is then removed by treating the resulting cephalosporin withtrifluoroacetic acid and anisole. The α-amino compounds of formula IIare taught in various U.S. patents as for example, U.S. Pat. Nos.3,485,819; 3,507,861; 3,641,021; 3,796,801; 3,813,388; 3,821,207; etc.

Similarly, the 7α-methoxy compounds of formula I (R₁ is methoxy) whereinX is hydrogen, lower alkanoyloxy, or heterothio can be prepared byreacting an α-amino intermediate of the formula ##STR16## preferably inthe form of its trifluoroacetic acid salt with a compound of formulaIII, IV, or V.

The 7α-methoxy intermediate of formula VIII can be prepared in ananalogous manner to the compound of formula II, i.e. by acylating a7α-methyl-7β-amino-cephalosporin of the formula ##STR17## with asubstituted α-amino acid of formula VII followed by removal of theprotecting group. The compounds of formula IX are taught in U.S. Pat.No. 3,897,424 and the preparation of the compound of formula VIII byvarious other methods are taught in U.S. Pat. Nos. 3,775,410; 3,780,031;3,780,033; 3,780,034; 3,780,037; 3,887,549; etc.

The compound of formula I wherein R₁ is either hydrogen or methoxy and Xis pyridinium or carbamoyl substituted pyridinium are prepared byreacting the compound of the formula ##STR18## with pyridine orcarbamoyl substituted pyridine in a polar solvent such as water and inthe presence of a catalyst such as an alkali metal thiocyanate. U.S.Pat. No. 3,792,047 and German Offenlegungsschrift No. 2,234,280 bothdisclose methods for reacting a cephalosporin so as to replace anacetoxy group with a pyridinium group.

Also, the compounds of formula I wherein R₁ is either hydrogen ormethoxy and X is heterothio can be prepared by reacting the compound offormula Ib with a mercaptan of the formula

    hetero--S--H                                               (X)

or an alkali metal (preferably sodium) mercaptan salt of the formula

    hetero--S--alkali metal.                                   (XI)

methods for displacing the acetoxy group of a cephalosporin by aheterothio group are taught in various U.S. patents including U.S. Pat.Nos. 3,855,213; 3,890,309; 3,892,737; etc.

The compounds of formula I wherein X is hydrogen, lower alkanoyloxy, orheterothio can also be prepared by reacting a compound of the formula##STR19## with an ester, preferably R is diphenylmethyl, of the compoundof formula VI or IX in the presence of hydroxybenzotriazole. Theresulting ester is then treated according to methods known in the art toyield the corresponding compound of formula I wherein R is hydrogen.

The compound of formula XII can be prepared by reacting theisocyanatoacetic acid ester of the formula ##STR20## with the compoundof the formula ##STR21##

The compounds of formula I wherein R is lower alkyl, phenyl-lower alkyl,trihaloethyl, diphenyl-lower alkyl, or the acyloxymethyl group ##STR22##may be obtained by reacting the 7-amino cephalosporin of formula VI orIX either before or after the acylation of the 7-amino substituent withone or two moles of a compound of the formula

    halo--R                                                    (XV)

or

    R=N.sup.+=N.sup.-                                          (XVI)

wherein halo is preferably chlorine or bromine in an inert solvent suchas dimethylformamide, acetone, dioxane, benzene, or the like at aboutambient temperature or below.

Similarly, the compounds of formula I wherein R is tri(lower alkyl)silyl are obtained by introducing such groups onto the cephalosporanicacid moiety either before or after the acylation reaction.

The carboxylate salts of the compound of formula I are formed byreacting the carboxyl group of the cephalosporanic acid moiety, i.e. Ris hydrogen, with any of the salt forming ions described above.

It will be appreciated that the compounds of formula I are opticallyactive due to the presence of an asymmetric carbon atom represented asC* in the preceding formulas. By selection of the appropriate startingmaterial it is possible to obtain the compounds of formula I as amixture of optically active isomers or isolated as a single isomer. Thevarious isomers as well as their mixtures are within the scope of thisinvention.

Preferred compounds of this invention are the acids and alkali metalsalts of formula I (i.e. R is hydrogen, sodium, or potassium) wherein Xis pyridinium, carbamoyl substituted pyridinium (particularly where thecarbamoyl group is in the 4-position), or heterothio; R₄ iscyclohexenyl, cyclohexadienyl, phenyl, benzyl, phenethyl, substitutedphenyl, benzyl, or phenethyl wherein the substituent is on the phenylring and is one or two members selected from chloro, bromo, methyl,ethyl, methoxy, ethoxy and hydroxy, or a substituted or unsubstitutedheterocyclic selected from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,2-pyridyl, 3-pyridyl and 4-pyridyl wherein the heterocyclic substituentis chloro, bromo, methyl, or ethyl; R₂ is straight or branched chainalkenyl or alkinyl of 2 to 4 carbons; and R₃ is hydrogen or straight orbranched chain alkyl of 1 to 4 carbons.

Also preferred as both final products and intermediates are thecompounds of formula I wherein X is ##STR23## and R₂, R₃, and R₄ are asdefined above.

The most preferred final compounds are the acids and alkali metal saltsof formula I wherein R₄ is 2-thienyl, 3-thienyl, phenyl, or4-hydroxyphenyl; X is heterothio, particularly wherein X is ##STR24##and R₂ is straight or branched chain alkenyl of 2 to 4 carbons.

The acid compounds of formula I have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aureus, Salmonella schottmuelleri, Proteus rettgeri,Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, etc. Theymay be used as antibacterial agents in a prophylactic manner, e.g., incleaning or as surface disinfecting compositions, or otherwise to combatinfections due to organisms such as those named above, and in generalmay be utilized in a manner similar to cephalothin and othercephalosporins. For example, a compound of formula I or aphysiologically acceptable salt thereof may be used in various animalspecies in an amount of about 1 to 100 mg./kg., daily, orally orparenterally, in single or two to four divided doses to treat infectionsof bacterial origin, e.g., 5.0 mg./kg. in mice.

Up to about 600 mg. of an acid compound of formula I or aphysiologically acceptable salt thereof may be incorporated in an oraldosage form such as tablets, capsules or elixirs or in an injectableform in a sterile aqueous vehicle prepared according to conventionalpharmaceutical practice.

They may also be used in cleaning or disinfecting compositions, e.g.,for cleaning barns or dairy equipment, at a concentration of about 0.2to 1% by weight or such compounds admixed with, suspended or dissolvedin conventional inert dry or aqueous carriers for application by washingor spraying.

They are also useful as nutritional supplements in animal feeds.

Illustrative process details are provided in the examples for thevarious reactions. All temperatures are on the centigrade scale.

EXAMPLE 17β-[[D-[[(2-Propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) D-α-[[(2-Propenylamino)carbonyl]amino]-2-thiopheneacetic acid,4-nitrophenyl ester

To a solution of 0.01 mole of D-α-isocyanato-2-thiopheneacetic acid,4-nitrophenyl ester in 20 ml. of tetrahydrofuran is added dropwise atroom temperature over 30 minutes a solution of 0.63 g. of2-propen-1-amine in 10 ml. of tetrahydrofuran. The mixture is stirredfor one hour. After concentrating the solution and treating the residuewith ether, 3.4 g. ofD-α-[[(2-propenylamino)carbonyl]amino]-2-thiopheneacetic acid,4-nitrophenyl ester are obtained as an amorphous powder; m.p. 98°-102°.

(b)7β-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a stirred suspension of 27.2 g. 7-amino cephalosporanic acid (0.1mole) in 150 ml. of acetone and 100 ml. of H₂ O at 0°-5° is added 50 ml.of 2N NaOH, with care being taken to keep the pH below 8.5. A solutionof 12.7 g. (0.11 mole) of 1-methyl-5-mercapto-1H-tetrazole in 50 ml. of2N NaOH is added, and the mixture is allowed to warm to roomtemperature. The stirred mixture is then maintained at 60° (internaltemperature) under nitrogen for 3 hours at pH 7-7.5 by the periodicaddition of dilute aqueous NaOH. The mixture is cooled in an ice-waterbath, and while stirring, 3N HCl is added to adjust the pH to 3.9.Stirring is continued for 15 minutes, and the precipitate is collectedby filtration, washed with water, and then acetone, and finally dried togive the desired product as a powder (18.4 g.).

(c)7β-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

A mixture of 16.4 g. (0.05 mole) of the acid product from part (b), 10.3g. (0.054 mole) p-toluenesulfonic acid monohydrate, 350 ml. of dioxane(dried by passage through basic alumina), and dry CH₃ OH is stirred atroom temperature under nitrogen for 30 minutes. The clear solution isevaporated to a residue, and H₂ O and CH₃ OH are removed by fourevaporations of 100 ml. quantities of dioxane. Fresh dioxane (300 ml.)is then added to the residue followed by a solution of crystallinediphenyldiazomethane (19.4 g., 0.10 mole) in 150 ml. of drydimethoxyethane. The mixture is initially shaken vigorously for 10-15minutes and then stirred at room temperature for 3 hours. Methanol (25ml.) is added, and the red solution is stirred until it has turnedyellow-orange. The solvents are removed in vacuo, and the residue istreated with 400 ml. of CH₂ Cl₂ and a solution of 20 g. of K₂ HPO.sub. 4in 250 ml. of H₂ O. The CH₂ Cl₂ layer is washed with water and saturatedNaCl, and finally dried (MgSO₄) to give a residue after removal of thesolvent in vacuo. Treatment of the residue with Et₂ O gives a solid (27g.). Column chromatography of this solid on silica gel by elution withCHCl₃ and then EtOAc--CHCl₃ (4:1) provides the desired product as aresidue (12.9 g.). Treatment with EtOAc then provides 8.0 g. of thedesired product as a pale yellow powder.

(d)7β-[[D-[[(2-Propenylamino)carbonyl]amino]-2-thienylacetyl]-amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

1.48 g. (0.003 mole) of7β-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylicacid, diphenylmethyl ester from part (c) are dissolved in 20 ml. ofmethylene chloride and a solution of 1.15 g. (0.0035 mole) ofD-α-[[(2-propenylamino)carbonyl]-amino]-2-thiopheneacetic acid,4-nitrophenyl ester from part (a) in 10 ml. of N,N-dimethylacetamide isadded. After the addition of 0.49 g. (0.003 mol.) ofhydroxybenzotriazole, the solution is stirred overnight at roomtemperature. The reaction solution is diluted with 250 ml. ofethylacetate, washed with sodium bicarbonate solution and with water,dried with magnesium sulfate and concentrated in vacuum. The residue istriturated with ether and filtered under suction to obtain 1.5 g. of7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienyl-acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester as ayellow-brown amorphous powder; m.p. 116°.

(e)7β-[[D-[[(2-Propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

1.6 g. of the diphenylmethyl ester product from part (d) is reacted with10 ml. of anisole and 17 ml. of trifluoroacetic acid at 0°-5° for 10minutes to obtain 1.2 g. of7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2 -ene-2-carboxylic acid as a yellow-brown powder; m.p. 120° (dec.).

An aqueous equimolar solution of this acid and sodium bicarbonate islyophilized to yield7β-[[D-[[2-propenylamino)-carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, sodium salt; m.p. 160°-163° (dec.).

In an analogous manner, by substituting L-α-isocyanato- 2-thienylaceticacid, 4-nitrophenyl ester for the D-isomer in part (a) and thenfollowing the procedure of Example 1, one obtains7β-[[L-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and its sodium salt.

EXAMPLE 27α-Methoxy-7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a)7α-Methoxy-7β-[[D-[[(2-propenlyamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

D-α-[[(2-Propenylamino)cabonyl]amino]-2-thiopheneacetic acid,4-nitrophenyl ester from example 1(a) and 7α-methoxy-7β-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester are reacted according to the procedure ofexample 1 (d) to yield 7α-methoxy-7β-[[D-[[(2-propenylamino)-carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-caraboxylicacid, diphenylmethyl ester.

(b)7α-Methoxy-7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The diphenylmethyl ester product from part (a) is treated with anisoleand trifluoroacetic acid according to the procedure of example 1 (e) toyield7α-methoxy-7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

An aqueous equimolar solution of this acid and sodium bicarbonate islyophilized to yield7α-methoxy-7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, sodium salt.

In an analogous manner one can obtain, 7α-methoxy-7β-[[L-[[(2-propenylamino)carabonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-caboxylicacid and its sodium salt.

EXAMPLES 3-50

Following the procedure of example 1 but employing the isocyanatocompound of Col. I and the amine of Col. II one obtains the nitrophenylester of Col. III. The ester of Col. III and the 7β-amino-7α-methoxy ordesmethoxy-cephalosporanic acid ester of Col. IV are reacted to yieldthe acylated cephalosporanic acid ester of Col. V. The ester of Col. Vcan be treated to remove the ester protecting group and yield thecephalosporanic acid of Col. VI which can be converted by known means toyield the corresponding salt. ##STR25##

    __________________________________________________________________________    Ex.                                                                              R.sub.4       R.sub.2     R.sub.3                                                                              R.sub.1                                                                            R          X                         __________________________________________________________________________     3                                                                                             CH.sub.2CHCH.sub.2                                                                        CH.sub.3                                                                             H                                                                                   ##STR26##                                                                                ##STR27##                 4                                                                                ##STR28##    CH.sub.2CHCH.sub.2                                                                        CH.sub.3                                                                             OCH.sub.3                                                                           ##STR29##                                                                                ##STR30##                 5                                                                                ##STR31##    CHCH.sub.2  H      H                                                                                   ##STR32##                                                                                ##STR33##                 6                                                                                ##STR34##    CHCH.sub.2  H      OCH.sub.3                                                                           ##STR35##                                                                                ##STR36##                 7                                                                                ##STR37##                                                                                   ##STR38##  H      H    CH.sub.2 CCl.sub.3                                                                        ##STR39##                 8                                                                                ##STR40##    CH.sub.2CHCHCH.sub.3                                                                      H      OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                           ##STR41##                 9                                                                                ##STR42##    CH.sub.2CHCHCH.sub.3                                                                      C.sub.2 H.sub.5                                                                      H                                                                                   ##STR43##                                                                                ##STR44##                10                                                                                ##STR45##                                                                                   ##STR46##  H      H                                                                                   ##STR47##                                                                                ##STR48##                11                                                                                ##STR49##                                                                                   ##STR50##  H      H                                                                                   ##STR51##                                                                                ##STR52##                12                                                                                ##STR53##    CHCHCH.sub.2                                                                              OCH.sub.3                                                                            OCH.sub.3                                                                          CH.sub.2 CCl.sub.3                                                                        ##STR54##                13                                                                                ##STR55##                                                                                   ##STR56##  H      H                                                                                   ##STR57##                                                                                ##STR58##                14                                                                                ##STR59##                                                                                   ##STR60##  C.sub.2 H.sub.5                                                                      OCH.sub.3                                                                           ##STR61##                                                                                ##STR62##                15                                                                                ##STR63##                                                                                   ##STR64##  H      H                                                                                   ##STR65##                                                                                ##STR66##                16                                                                                ##STR67##                                                                                   ##STR68##  CH.sub.3                                                                             OCH.sub.3                                                                           ##STR69##                                                                                ##STR70##                17                                                                                ##STR71##                                                                                   ##STR72##  H      H                                                                                   ##STR73##                                                                                ##STR74##                18                                                                                ##STR75##    CH.sub.2CHCH.sub.2                                                                         ##STR76##                                                                           H                                                                                   ##STR77##                                                                                ##STR78##                19                                                                                ##STR79##    CHCH.sub.2  H      OCH.sub.3                                                                           ##STR80##                                                                                ##STR81##                20                                                                                ##STR82##                                                                                   ##STR83##  CH.sub.3                                                                             H                                                                                   ##STR84##                                                                                ##STR85##                21                                                                                ##STR86##                                                                                   ##STR87##  H      H                                                                                   ##STR88##                                                                                ##STR89##                22                                                                                ##STR90##                                                                                   ##STR91##  C.sub.2 H.sub.5                                                                      OCH.sub.3                                                                           ##STR92##                                                                                ##STR93##                23                                                                                ##STR94##                                                                                   ##STR95##  H      OCH.sub.3                                                                          CH.sub.2 CCl.sub.3                                                                        ##STR96##                24                                                                                ##STR97##    CHCH.sub.2  C.sub.2 H.sub.5                                                                      H                                                                                   ##STR98##                                                                                ##STR99##                25                                                                                ##STR100##   CH.sub.2CHCH.sub.2                                                                        H      H                                                                                   ##STR101##                                                                               ##STR102##               26                                                                                ##STR103##   CH.sub.2CHCH.sub.2                                                                        CH.sub.3                                                                             OCH.sub.3                                                                           ##STR104##                                                                               ##STR105##               27                                                                                ##STR106##   CHCH.sub.2  H      OCH.sub.3                                                                           ##STR107##                                                                               ##STR108##               28                                                                                ##STR109##   CHCH.sub.2  H      H                                                                                   ##STR110##                                                                               ##STR111##               29                                                                                ##STR112##   CHCH.sub.2  C.sub.2 H.sub.5                                                                      OCH.sub.3                                                                          CH.sub.2 CCl.sub.3                                                                        ##STR113##               30                                                                                ##STR114##                                                                                  ##STR115## H      H                                                                                   ##STR116##                                                                               ##STR117##               31                                                                                ##STR118##                                                                                  ##STR119## H      OCH.sub.3                                                                           ##STR120##                                                                               ##STR121##               32                                                                                ##STR122##                                                                                  ##STR123## C.sub.3 H.sub.7                                                                      H                                                                                   ##STR124##                                                                               ##STR125##               33                                                                                ##STR126##                                                                                  ##STR127## H      OCH.sub.3                                                                           ##STR128##                                                                               ##STR129##               34                                                                                ##STR130##                                                                                  ##STR131## CH.sub.3                                                                             H                                                                                   ##STR132##                                                                               ##STR133##               35                                                                                ##STR134##   CHCH.sub.2  H      OCH.sub.3                                                                           ##STR135##                                                                               ##STR136##               36                                                                                ##STR137##                                                                                  ##STR138## H      H                                                                                   ##STR139##                                                                               ##STR140##               37                                                                                ##STR141##                                                                                  ##STR142## H      OCH.sub.3                                                                           ##STR143##                                                                               ##STR144##               38 H             CH.sub.2CHCHCH.sub.3                                                                      C.sub.2 H.sub.5                                                                      H                                                                                   ##STR145##                                                                               ##STR146##               39 C.sub.2 H.sub.5                                                                              ##STR147## H      OCH.sub.3                                                                           ##STR148##                                                                               ##STR149##               40                                                                                ##STR150##   CHCH.sub.2                                                                                 ##STR151##                                                                          H                                                                                   ##STR152##                                                                               ##STR153##               41                                                                                ##STR154##                                                                                  ##STR155## H      OCH.sub.3                                                                           ##STR156##                                                                               ##STR157##               42                                                                                ##STR158##   CH.sub.2CHCH.sub.2                                                                        CH.sub.3                                                                             H                                                                                   ##STR159##                                                                               ##STR160##               43                                                                                ##STR161##                                                                                  ##STR162## H      OCH.sub.3                                                                           ##STR163##                                                                               ##STR164##               44                                                                                ##STR165##                                                                                  ##STR166## H      H                                                                                   ##STR167##                                                                               ##STR168##               45                                                                                ##STR169##                                                                                  ##STR170## CH.sub.3                                                                             H                                                                                   ##STR171##                                                                               ##STR172##               46                                                                                ##STR173##   CH.sub.2CHCH.sub.2                                                                        H      H                                                                                   ##STR174##                                                                               ##STR175##               47                                                                                ##STR176##                                                                                  ##STR177## H      OCH.sub.3                                                                           ##STR178##                                                                               ##STR179##               48                                                                                ##STR180##                                                                                  ##STR181## H      H    Si(CH.sub.3).sub.3                                                                        ##STR182##               49                                                                                ##STR183##                                                                                  ##STR184## CH.sub.3                                                                             OCH.sub.3                                                                          Si(CH.sub.3).sub.3                                                                        ##STR185##               50                                                                                ##STR186##                                                                                  ##STR187## C.sub.2 H.sub.5                                                                      H                                                                                   ##STR188##                                                                               ##STR189##               __________________________________________________________________________     The isocyanato compounds of Col. I may be in either the D- or L- form or      may be a mixture of the D- and L- isomers.                               

The isocyanato compounds of Col. I may be in either the D- or L- form ormay be a mixture of the D- and L- isomers.

EXAMPLE 51β-[[D-[[[(Ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) D-2-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneaceticacid

74 g. of D-2-Thienylglycine are dissolved in 940 ml. of water. 37.8 g.of magnesium oxide are added and to this resulting suspension a solutionof 107.5 g. of p-methoxybenzyloxycarbonylazide in 940 ml. of dioxane isadded with stirring. The mixture is stirred at room temperature for 24hours. It is then filtered and the filtrate is extracted with 600 ml. ofether. The extract is discarded. The water is dioxane phase is layeredover with 600 ml. of ethyl acetate, cooled to 5° and brought to pH 2with 2N hydrochloric acid. The layers are separated and the aqueouslayer is again extracted with 300 ml. of ethyl acetate. The combinedethyl acetate extracts are washed with water, dried with magnesiumsulfate, filtered and concentrated. The oily residue crystallizes upontrituration with petroleum ether to yield 118 g. ofD-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid;m.p. 84°-94°; [α]₂₀.sup. D : - 69° (c=1, tetrahydrofuran).

(b)7β-[[D-[[[(4-Methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

46.2 g. of7β-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2carboxylicacid, diphenylmethyl ester from example 1(c) are dissolved in 550 ml. ofanhydrous methylene chloride. 550 ml. of tetrahydrofuran and 36 g. ofD-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid,from part (a), are added. The reaction solution is cooled to 0° and asolution of 22.5 g. of dicyclohexylcarbodiimide in 150 ml. of anhydroustetrahydrofuran is added dropwise over the course of 30 minutes. Themixture is then stirred for 90 minutes at 0° and finally 120 minutes atroom temperature. The precipitated dicyclohexylurea (21 g.) is filteredoff under suction and the filtrate is concentrated. The residue is takenup in a mixture of 1000 ml. of ethyl acetate and 400 ml. oftetrahydrofuran, filtered and the filtrate is washed first with sodiumbicarbonate solution and then with water. This is then dried withmagnesium sulfate, treated with activated carbon, filtered and thefiltrate is then concentrated slowly under vacuum to a small volume.After standing overnight in the refrigerator, the precipitate crystalsare filtered under suction to obtain 63.1 g. of7β-[[D-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester; m.p. 130°-131° (dec.). [α]₂₀.sup. D : -117°(c=1, tetrahydrofuran).

(c)7β-[D-2-Amino-2-(2-thienyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt (1:1)

62 g. of the diphenylmethyl ester product from part (b) are added to 300ml. of anisole with stirring. The mixture is cooled to 0° and 750 ml. oftrifluoroacetic acid are added slowly. The mixture is stirred for 10minutes at 0° and the anisole is evaporated at 0.1 mm. of Hg. and 35°bath temperature. The residue is treated with 250 ml. of petroleumether, then 350 ml. of ether, stirred for one hour, and filtered withsuction to yield 46.4 g. of7β-[D-2-amino-2-(2-thienyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt (1:1); m.p. 138°-139° (dec.).

(d)7β-[[D-[[(Ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

0.01 mole of the trifluoroacetic salt product from part (c) aresuspended in methylene chloride and 0.02 mole of triethylamine areadded. To the almost clear solution is added dropwise at 0°-5°, 0.012mole of a solution of isocyanatoethene and methylene chloride. Afterstirring for one hour, the reaction solution is concentrated, theresidue is dissolved in water, filtered, and acidified with 2Nhydrochloric acid to yield as a precipitate,7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

An aqueous equimolar solution of this acid and sodium bicarbonate islyophilized to yield7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, sodium salt.

In an analogous manner by substituting L-2-thienylglycine for theD-isomer in part (a) and then following the procedure of example 51, oneobtains7β-[[L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and its sodium salt.

EXAMPLE 527α-Methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a)7α-Methoxy-7β-[[D,L-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

2.41 g. (0.0075 mole) ofD,L-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acid(prepared according to the procedure of example 51 (a)) is dissolved in50 ml. of dry methylene chloride, the solution is cooled in an ice bathto 0°- 5°, and 0.969 g. (0.0075 mole) of diisopropylethylamine andisobutylchloroformate are added to the cold solution. After 10 minutes,3.28 g. (0.00625 mole) of7β-amino-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester is added to the reaction mixture and the icebath is removed. Following three hours of stirring at room temperature,a second portion of mixed anhydride is prepared in a separate flaskusing the procedure described above. This solution is added to thereaction mixture and after 4.5 hours another batch of mixed anhydrideprepared using half the quantities set forth above is added to the mainreaction mixture. Stirring is continued at room temperature for 12 hoursand the reaction mixture is then diluted with methylene chloride andwashed with water, saturated aqueous sodium bicarbonate solution, andwater. The organic layer is dried over sodium sulfate and the solvent isremoved in vacuo to yield a foam. This crude product is chromatographedon silica gel (200 g., 60-200 mesh) and the desired product is elutedwith 9:1 and 4:1 methylene chloride:ethyl acetate. The oily product isprecipitated as a powder from a methylene chloride-ether mixture anddried over phosphorous pentoxide in vacuo to yield 3.81 g. of7α-methoxy-7β-[[D,L-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester. Alternatively, the titledcompound can be obtained by the following procedure.

129 mg. (0.4 mmole) ofD,L-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acidis dissolved in 2 ml. of anhydrous methylene chloride and 47 mg. (0.2mmole) of dicyclohexylcarbodiimide is added. The mixture is stirred for15 minutes at room temperature during which time colorlessdicyclohexylurea crystallizes. The suspension is directly filtered intoa stirring solution of 77 mg. (0.147 mmole) of7β-amino-7α-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester in 1 ml. of methylene chloride. Afterstirring at room temperature for 19 hours, the mixture is diluted withmethylene chloride, washed with pH 7.4 buffer, and dried over sodiumsulfate. Removal of solvent under reduced pressure yields a crude oilwhich is chromatographed on preparative thin layer chromatography silicagel plates developed in a 4:1 chloroform:ethyl acetate mixture. Thedesired product (58 mg.) is isolated as an oil.

(b)7α-Methoxy-7β-[D,L-2-amino-2-(2-thienyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt (1:1)

The diphenylmethyl ester product from part (a) is reacted withtrifluoroacetic acid in the presence of anisole according to theprocedure of example 51(c) to yield the titled compound.

(c)7α-Methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

The trifluoroacetic acid salt product from part (b) is reacted withisocyanatoethene according to the procedure of example 51(d) to yield7α-methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

An aqueous equimolar solution of this acid and sodium bicarbonate islyophilized to yield7α-methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.

EXAMPLES 53-77

Following the procedure of example 51 but employing the acylating agentshown in Col. I and the 7β-amino-7α-methoxy ordesmethoxy-cephalosporanic acid ester shown in Col. II, one obtains theprotected ester shown in Col. III. The protecting group and ester groupare removed as the compound of Col. III is converted to itstrifluoroacetic acid salt shown in Col IV. The trifluoroacetic acid saltis reacted with the isocyanato compound of Col. V to yield thecephalosporanic acid shown in Col. VI. The acid of Col. VI can bereacted so as to reintroduce the ester group and yield the compound ofCol. VII or can be treated according to known procedures to yield thecorresponding salt. ##STR190##

Alternatively, the α-aminocephalosporanic acid ester of Col. VIII can betreated with the compound of Col. V to yield the ester of Col. VII. Thisester can then be treated to remove the ester group and yield thecephalosporanic acid of Col. VI. ##STR191##

    __________________________________________________________________________    Ex. R.sub.4     R.sub.2    R.sub.1  R           X                             __________________________________________________________________________    53                                                                                          CH.sub.2CHCH.sub.2                                                                         H                                                                                    ##STR192##                                                                                ##STR193##                      54                                                                                ##STR194##                                                                               ##STR195##  OCH.sub.3                                                                            ##STR196##                                                                                ##STR197##                      55                                                                                ##STR198##                                                                              CH.sub.2CCH  H                                                                                    ##STR199##                                                                                ##STR200##                      56                                                                                ##STR201##                                                                              CH.sub.2CCCH.sub.3                                                                         OCH.sub.3                                                                            ##STR202##                                                                                ##STR203##                      57                                                                                ##STR204##                                                                               ##STR205##  H     t-C.sub.4 H.sub.9                                                                          ##STR206##                      58                                                                                ##STR207##                                                                              CHCH.sub.2   H                                                                                    ##STR208##                                                                                ##STR209##                      59                                                                                ##STR210##                                                                               ##STR211##  OCH.sub.3                                                                            ##STR212##                                                                                ##STR213##                      60                                                                                ##STR214##                                                                               ##STR215##  H                                                                                    ##STR216##                                                                                ##STR217##                      61                                                                                ##STR218##                                                                              CH.sub.2CH CHCH.sub.3                                                                      H                                                                                    ##STR219##                                                                                ##STR220##                      62                                                                                ##STR221##                                                                              CH.sub.2CHCH.sub.2                                                                         OCH.sub.3                                                                           C.sub.2 H.sub.5                                                                            ##STR222##                      63                                                                                ##STR223##                                                                               ##STR224##  H                                                                                    ##STR225##                                                                                ##STR226##                      64                                                                                ##STR227##                                                                              CH.sub.2CHCH.sub.2                                                                         OCH.sub.3                                                                            ##STR228##                                                                                ##STR229##                      65                                                                                ##STR230##                                                                              CH.sub.2CCCH.sub.3                                                                         H                                                                                    ##STR231##                                                                                ##STR232##                      66                                                                                ##STR233##                                                                              CHCH.sub.2   H                                                                                    ##STR234##                                                                                ##STR235##                      67                                                                                ##STR236##                                                                              CH.sub.2CCH  OCH.sub.3                                                                            ##STR237##                                                                                ##STR238##                      68                                                                                ##STR239##                                                                               ##STR240##  H                                                                                    ##STR241##                                                                                ##STR242##                      69                                                                                ##STR243##                                                                              CH.sub.2CCCH.sub.3                                                                         OCH.sub.3                                                                           t-C.sub.4 H.sub.9                                                                          ##STR244##                      70                                                                                ##STR245##                                                                              CH.sub.2CHCH.sub.2                                                                         H                                                                                    ##STR246##                                                                                ##STR247##                      71                                                                                ##STR248##                                                                              CH.sub.2CCCH.sub.3                                                                         OCH.sub.3                                                                            ##STR249##                                                                                ##STR250##                      72                                                                                ##STR251##                                                                               ##STR252##  H     CH.sub.2 CCl.sub.3                                                                         ##STR253##                      73                                                                                ##STR254##                                                                              CH.sub.2CCCH.sub.3                                                                         H                                                                                    ##STR255##                                                                                ##STR256##                      74                                                                                ##STR257##                                                                               ##STR258##  OCH.sub.3                                                                            ##STR259##                                                                                ##STR260##                      75                                                                                ##STR261##                                                                               ##STR262##  H                                                                                    ##STR263##                                                                                ##STR264##                      76                                                                                ##STR265##                                                                              CH.sub.2CHCHCH.sub.3                                                                       OCH.sub.3                                                                           Si(CH.sub.3).sub.3                                                                         ##STR266##                      77                                                                                ##STR267##                                                                              CH.sub.2CCCH.sub.3                                                                         H     Si(CH.sub.3).sub.3                                                                         ##STR268##                      __________________________________________________________________________

EXAMPLE 787β-[[D-[[(Ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[4-(aminocarbonyl)pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

(a)3-[(Acetyloxy)methyl-7β-[D-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

3.2 g. (0.01 mole) of theD-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acidfrom example 51(a) are brought into solution in 40 ml. of methylenechloride with 1.1 ml. of N-methylmorpholine. The solution is cooled to-15°, 1.39 ml. of isobutylchloroformate are added, and the mixture isstirred for 10 minutes. To this is added a solution of 3.26 g. (0.1012mol) of 7-aminocephalosporanic acid and 3.1 ml. of triethylamine in 140ml. of methylene chloride. The mixture is stirred for 1 hour at -5° and1 hour at 5°. This mixture is then evaporated to dryness in a rotaryevaporator. The solid residue is triturated with ether and filteredunder suction. The substance is then dissolved in ice water, layeredover with ethyl acetate and acidified to pH 2.5. The layers areseparated, the aqueous layer is extracted once more with ethyl acetate,the combined ethyl acetate extracts are washed with water, dried withmagnesium sulfate and concentrated. The residue (4.9 g.) is dissolved in200 ml. of ethyl acetate and the solution is treated with activatedcarbon. After filtration, 2 g. of3-[(acetyloxy)methyl]7β[[D-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, crystallize; m.p. 142°-143° (dec.).

(b)3-[(Acetyloxy)methyl]-7β-[D-2-amino-2-(2-thienyl)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt (1:1)

2.0 g. of the product from part (a) are added at -5° to a mixture of 10ml. of trifluoroacetic acid and 4 ml. of anisole. The mixture is stirredfor 10 minutes and is then concentrated in a rotary evaporator. Theresidue is treated with ether and filtered to yield the titled compound.

(c)3-[(Acetyloxy)methyl]-7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, sodium salt

The trifluoroacetic acid salt product from part (b) is treated withisocyanatoethene according to the procedure of example 51(d) to yield3-[(acetyloxy)methyl]-7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

An equimolar aqueous solution of this compound and sodium bicarbonate islyophilized to yield3-[(acetyloxy)methyl]-7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, sodium salt as a powder.

(d)7β-[[D-[[(Ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-2-thienylacetyl]amino]-3-[[4-(aminocarbonyl)pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 0.0005 mole of the sodium salt product of part (c), 0.0075mole of 4-pyridinecarboxamide, 12 g. of potassium thiocyanate, and 7.5ml. of water are heated at 50° for 24 hours. The clear solution ispassed through a chromatography column filled with 150 g. of ionexchanger Amberlite XAD-2. The column is washed with about 3 liters ofwater and the titled compound is eluted with a mixture of water:methanol(8:2). The methanol is evaporated from the eluate and the aqueoussolution is lyophilized. The amorphous residue is triturated with etherand filtered under suction to yield7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[4-(aminocarbonyl)pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Similarly, by employing theL-2-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thiopheneacetic acidin place of the D-isomer in the above procedure, one obtains7β[[L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[4-(aminocarbonyl)pyridino]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLES 79-93

Following the procedures of example 78, but employing thecephalosporanic acid sodium salt shown below in Col. I and the pyridinecompound shown in Col. II, one obtains the product shown in Col. III.##STR269##

    __________________________________________________________________________    Ex.  R.sub.1                                                                              R.sub.2    R.sub.3                                                                             R.sub.4   Z                                      __________________________________________________________________________    79  H     CHCH.sub.2   H                                                                                            ##STR270##                              80  OCH.sub.3                                                                           CH.sub.2CCH  H                                                                                   ##STR271##                                                                             ##STR272##                              81  OCH.sub.3                                                                           CH.sub.2CHCH.sub.2                                                                         H                                                                                   ##STR273##                                                                            H                                        82  OCH.sub.3                                                                           CH.sub.2CCCH.sub.3                                                                         H                                                                                   ##STR274##                                                                            H                                        83  H     CH.sub.2CHCHCH.sub.3                                                                       CH.sub.3                                                                            ##STR275##                                                                             ##STR276##                              84  OCH.sub.3                                                                            ##STR277##  H                                                                                   ##STR278##                                                                             ##STR279##                              85  H                                                                                    ##STR280##  C.sub.2 H.sub.5                                                                     ##STR281##                                                                             ##STR282##                              86  OCH.sub.3                                                                            ##STR283##  i-C.sub.3 H.sub.7                                                                   ##STR284##                                                                            H                                        87  H                                                                                    ##STR285##  H                                                                                   ##STR286##                                                                             ##STR287##                              88  OCH.sub.3                                                                           CHCH.sub.2   CH.sub.3                                                                            ##STR288##                                                                            H                                        89  H     CH.sub.2CHCH.sub.2                                                                         H                                                                                   ##STR289##                                                                             ##STR290##                              90  OCH.sub.3                                                                           CH.sub.2CCH  CH.sub.3                                                                            ##STR291##                                                                            H                                        91  H                                                                                    ##STR292##  H                                                                                   ##STR293##                                                                            H                                        92  OCH.sub.3                                                                            ##STR294##  CH.sub.3                                                                            ##STR295##                                                                             ##STR296##                              93  H                                                                                    ##STR297##  H                                                                                   ##STR298##                                                                             ##STR299##                              __________________________________________________________________________

The cephalosporanic acid sodium salts shown above in Col. I may be inthe D- or L-isomer form or a mixture of D- and L- isomers.

EXAMPLE 94 7β-[[D-[[ (Ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-oxo-2-pyridinyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

0.003 mole of 3-[(acetyloxy)methyl]-7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl] amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt from example 78 (c) and0.004 mole of 2-mercaptopyridine, 1-oxide, sodium salt are dissolved in15 ml. of water and heated overnight at 50°. The reaction mixture isthen diluted with water, filtered, and the clear solution is adjusted toa pH of 2 by the addition of 2N hydrochloric acid. The resultingprecipitate is filtered under suction to obtain7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-oxo-2-pyridinyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Following the same procedure but employing3-[(acetyloxy)methyl]-7β-[[L-[[(ethenylamino(carbonyl]amino]-2-thienylacetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt, one obtains thecorresponding final product in the L- form.

Similarly, the various 3-[(acetyloxy)methyl- 7α-methoxy ordesmethoxy-7β-acylureido-cephalosporanic acid sodium salts shown in Col.I of examples 79 to 93 may be employed in the procedure of example 94 toobtain other 3-[[(1-oxo-2-pyridinyl)thio] methyl]-cephalosporins withinthe scope of the invention.

EXAMPLE 95 7β-[[D-[[(Ethenylamino)carbonyl]amino]-2thienylacetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

3-[(Acetyloxy)methyl] -6β-[[D-[[(ethenylamino)carbonyl]-amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]-oct-2-ene-2-carboxylic acid, sodium salt from example 78 (c) isdissolved in a mixture of acetone:water (1:1). 1-Oxopyridazine-3-thiol,sodium salt is added under nitrogen and the solution is heated forseveral hours at 60°. The solution is diluted with 150 ml. of water andacidified to pH 5 by the addition of 2N hydrochloric acid while cooling.A precipitate forms which is filtered under suction to yeild7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Following the same procedure but employing 3-[(acetyloxy)methyl]-7β-[[L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2-carboxylic acid, sodium salt, one obtains thecorresponding final product in the L-form.

EXAMPLES 96-104

Following the procedure of example 95 but substituting for the1-oxopyridazine-3-thiol one of the following:

2-oxopyridazine-3-thiol

6-methyl-1-oxopyridazine-3-thiol

6-methoxy-1-oxopyridazine-3-thiol

6-t-butyl-2-oxopyridazine-3-thiol

6-ethyl-2-oxopyridazine-3-thiol

6-hydroxy-1-oxopyridazine-3-thiol

6-hydroxy-2-oxopyridazine-3-thiol

6-chloro-1-oxopyridazine-3-thiol

6-chloro-2-oxopyridazine-3-thiol

one obtains:

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3[[(6-methyl-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-methoxy-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-t-butyl-2-oxopyridazin-3yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-ethyl-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-hydroxy-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-hydroxy-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-choloro-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,and

7β-[[D-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(6-chloro-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid,respectively.

Similarly, by employing 3-[(acetyloxy)methyl] -7β-[[L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt in place of the D-isomerin examples 95 to 104, the corresponding final products in the L-isomerform are obtained. Additionally, the various 3-[(acetyloxy)methyl]-7α-methoxy or desmethoxy-7β-acylureido-cephalosporanic acid sodiumsalts shown in Col. I of examples 79 to 93 may be employed in theprocedure of examples 95 to 104 to obtain other compounds within thescope of the invention.

EXAMPLE 105 7α-Methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

(a) [(Acetyloxy)methyl]-7α-methoxy-7β-[[D,L-[[[(4-methoxyphenyl)methoxy]carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

D,L-2-[[[(4-Methoxyphenyl)metoxy] carbonyl]amino]-2-thiopheneacetic acidand 3-[(acetyloxy)methyl]-7α-methoxy-7β-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester are reactedaccording to either of the procedures set forth in example 52(a) toyield the titled compound.

(b) 3-[(Acetyloxy)methyl]-7α-methoxy-7β-[D,L-2-amino-2-(2-thienyl)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid,trifluoroacetic acid salt (1:1)

The diphenylmethyl ester product from part (a) is reacted withtrifluoroacetic acid in the presence of anisole according to theprocedure of example 1(e) to yield the titled compound.

(c)3-[(Acetyloxy)methyl]-7α-methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[ 4.2.0]oct-2-carboxylic acid

The trifluoroacetic acid salt product from part (b) is treated withisocyanatoethene according to the procedure of example 51(d) to yield3-[(acetyloxy)methyl] -7α-methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-carboxylicacid.

(d) 7α-Methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

The product from part (c) is dissolved in a mixture of acetone:water(1:1) with the aid of 5N sodium hydroxide. The pH is adjusted to 7.6-8.0and 5mmol. of 1-methyl-1H-tetrazole-5-thiol is added. The pH ismaintained at 7.8 by the addition of 5N sodium hydroxide. The reactionmixture is heated at 50° to 60° for several hours. After cooling anddistilling off the acetone, the mixture is acidified to pH 2.5 by theaddition of 2N hydrochloric acid while cooling with ice. The resultingprecipitate is extracted with ethyl acetate to yield7α-methoxy-7β-[[D,L-[[(ethenylamino)carbonyl]amino]-2-thienylacetyl]amino] -3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

EXAMPLES 106-124

Following the procedure of example 105 but employing the3[(acetyloxy)methyl] -7α-methoxy or desmethoxy-7β-acylureidocephalosporanic acid shown below in Col. I and the heteromercaptan shownbelow in Col. II, one obtains the 3-heterothio compounds shown in Col.III. ##STR300##

    __________________________________________________________________________    Ex. R.sub.1 R.sub.2    R.sub.3  R.sub.4 hetero                                __________________________________________________________________________    106 H     CH.sub.2CHCH.sub.2                                                                         H                                                                                               ##STR301##                           107 H     CHCH.sub.2   CH.sub.3                                                                               ##STR302##                                                                             ##STR303##                           108 OCH.sub.3                                                                           CH.sub.2CCH  H                                                                                      ##STR304##                                                                             ##STR305##                           109 H                                                                                    ##STR306##  CH.sub.3                                                                               ##STR307##                                                                             ##STR308##                           110 H     CH.sub.2CCCH.sub.3                                                                         H                                                                                      ##STR309##                                                                             ##STR310##                           111 OCH.sub.3                                                                            ##STR311##  CH.sub.3                                                                               ##STR312##                                                                             ##STR313##                           112 H     CH.sub.2CHCHCH.sub.3                                                                       H                                                                                      ##STR314##                                                                             ##STR315##                           113 OCH.sub.3                                                                            ##STR316##  C.sub.2 H.sub.5                                                                        ##STR317##                                                                             ##STR318##                           114 H     CHCH.sub.2   H                                                                                      ##STR319##                                                                             ##STR320##                           115 H     CH.sub.2CCH  CH.sub.3                                                                               ##STR321##                                                                             ##STR322##                           116 OCH.sub.3                                                                            ##STR323##  C.sub.2 H.sub.5                                                                        ##STR324##                                                                             ##STR325##                           117 H     CH.sub.2CHCH.sub.2                                                                         H                                                                                      ##STR326##                                                                             ##STR327##                           118 OCH.sub.3                                                                           CH.sub.2CHCH.sub.2                                                                          ##STR328##                                                                            ##STR329##                                                                             ##STR330##                           119 H     CHCH.sub.2   C.sub.2 H.sub.5                                                                        ##STR331##                                                                             ##STR332##                           120 OCH.sub.3                                                                           CH.sub.2CCH  CH.sub.3                                                                              C.sub.2 H.sub.5                                                                         ##STR333##                           121 H     CH.sub.2C CC.sub.2 H.sub.5                                                                 CH.sub.3                                                                               ##STR334##                                                                             ##STR335##                           122 H                                                                                    ##STR336##  H                                                                                      ##STR337##                                                                             ##STR338##                           123 OCH.sub.3                                                                           CH.sub.2CHCHCH.sub.3                                                                       H                                                                                      ##STR339##                                                                             ##STR340##                           124 OCH.sub.3                                                                           CH.sub.2CCH  CH.sub.3                                                                               ##STR341##                                                                             ##STR342##                           __________________________________________________________________________

The 3-[(acetyloxy)methyl] -cephalosporanic acids of Col. I above may bein either the D- or L- isomer form or may be a mixture of the D- and L-isomers.

What is claimed is:
 1. A compound of the formula: ##STR343## wherein Ris hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl,tri(lower alkyl) silyl, trihaloethyl, an alkali metal ion, and alkalineearth metal ion, an alkaline earth metal ion, dibenzylamine,N,N-dibenzylethylenediamine, methylamine, triethylamino,N-ethylpiperidine or ##STR344## R₂ is lower alkenyl or lower alkinyl; R₃is hydrogen or lower alkyl; R₄ is phenyl, phenyl-lower alkyl,substituted phenyl or phenyl-lower alkyl wherein said phenyl substituentis one or two members selected from the group consisting of halogen,lower alky of 1 to 4 carbons lower alkoxy of 1 to 4 carbons, andhydroxy, or a substituted or unsubstituted heterocyclic selected fromthe group consisting of 2-thienyl, 3-thienyl, 2-furyl, and 3-furylwherein said heterocyclic substituent is attached at an available carbonatom and is halogen or lower alkyl of 1 to 4 carbons; R₅ is hydrogen orlower alkyl; R₆ is lower alkyl; and X is a heterothio group selectedfrom the group consisting of ##STR345## wherein R₇ is hydrogen or loweralkyl of 1 to 4 carbons and R₈ is hydrogen, lower alkyl of 1 4 carbons,methoxy, hydroxy,or halogen.
 2. The compound of claim 1 wherein R ishydrogen straight or branched chain alkyl of 1 to 4 carbons, benzyl,phenethyl, diphenylmethyl, trimethylsilyl, 2,2,2-trichloroethyl, analkali metal ion, and alkaline earth metal ion, dibenzylamine,N,N-dibenzylethylenediamine, methylamine, triethylamino,N-ethylpiperidine, or ##STR346## R₂ is lower alkenyl or lower alkinylwherein said alkenyl or alkinyl is straight or branched chain of 2 to 8carbons having one double or triple bond; R₃ is hydrogen or lower alkylwherein lower alkyl is straight or branched chain of 1 to 8 carbons; R₄is phenyl, benzyl, phenethyl, substituted phenyl, benzyl or phenethylwherein said substituent is on the phenyl ring and is one or two membersselected from the group consisting of chloro, bromo, methyl, ethyl,methoxy, ethoxy and hydroxy, or a substituted or unsubstitutedheterocyclic selected from the group consisting of 2-thienyl, 3-thienyl,2-furyl, and 3-furyl wherein said heterocyclic substituent is attachedat an available carbon atom and is chloro, bromo, methyl, or ethyl, R₅is hydrogen or straight or branched chain alkyl of 1 to 4 carbons; R₆ isstraight or branched chain alkyl of 1 to 4 carbons; and X is aheterothio group selected from the group consisting of ##STR347##wherein R₇ is hydrogen, methyl, or ethyl and R₈ is hydrogen, methyl,ethyl, methoxy, hydroxy, or chlorine.
 3. The compound of claim 2 whereinR is hydrogen, straight or branched chain alkyl of 1 to 4 carbons,benzyl phenethyl, diphenylmethyl, sodium or potassium; R₂ is loweralkenyl of lower alkinyl wherein said lower alkenyl or lower alkinyl isstraight or branched chain alkyl of 1 to 4 carbons; R₃ is hydrogen orstraight or branched chain alkyl of 1 to 4 carbons; R₄ is phenyl,benzyl, phenethyl, substituted phenyl, benzyl or phenethyl wherein saidsubstituent is on the phenyl ring and is one or two members selectedfrom the group consisting of chloro, bromo, methyl, ethyl, methoxy,ethoxy and hydroxy, or a substituted or unsubstituted heterocyclicselected from the group consisting of 2-thienyl, 3-thienyl,2-furyl, and3-furyl, wherein said heterocyclic substituent is attached at anavailable carbon atom and is chloro, bromo, methyl, or ethyl.
 4. Thecompound of claim 3 wherein R is hydrogen, sodium or potassium; R₄ is2-thienyl, 3-thienyl, phenyl or 4-hydroxyphenyl; and R₂ is lower alkenylof 2 to 4 carbons.
 5. The compound of claim 4 wherein X is ##STR348##and R₇ is hydrogen, methyl, or ethyl.
 6. The compound of claim 5 whereinR is hydrogen and R₇ is methyl.
 7. The compound of claim 4 wherein X is##STR349## and R₇ is hydrogen, methyl, or ethyl.
 8. The compound ofclaim 7 wherein R₇ is methyl and R is hydrogen.
 9. The compound of claim4 wherein X is ##STR350## and R₇ is hydrogen, methyl, or ethyl.
 10. Thecompound of claim 9 wherein R₇ is methyl and R is hydrogen.
 11. Thecompound of claim 4 wherein X is ##STR351## and R is hydrogen.
 12. Thecompound of claim 4 wherein X is ##STR352## and R₇ is hydrogen, methyl,or ethyl.
 13. The compound of claim 12 wherein R₇ is methyl and R ishydrogen.
 14. The compound of claim 4 wherein X is ##STR353## and R₇ ishydrogen, methyl, or ethyl.
 15. The compound of claim 14 wherein R₇ ismethyl and R is hydrogen.
 16. The compound of claim 4 wherein X is##STR354## and R₇ is hydrogen, methyl, or ethyl.
 17. The compound ofclaim 16 wherein R₇ is hydogen and R is hydrogen.
 18. The compound ofclaim 4 wherein X is ##STR355## and R₈ is hydrogen, methyl, ethyl,methoxy, hydroxy, or chlorine.
 19. The compound of claim 18 wherein R₈is hydrogen and R is hydrogen.
 20. The compound of claim 3 wherein X is##STR356## and R₇ is hydrogen, methyl, or ethyl.
 21. The compound ofclaim 20 wherein R₇ is methyl.
 22. The compound of claim 21 wherein R ishydrogen, diphenylmethyl, sodium, or potassium; R₄ is 2-thienyl,3-thienyl, phenyl or 4-hydroxyphenyl; and R₂ is lower alkenyl of 2 to 4carbons.
 23. The compound of claim 22 wherein R₄ is 2-thienyl.
 24. Thecompound of claim 23 wherein R₂ is --CH₂ --CH=CH₂.
 25. The compound ofclaim 24 wherein R is diphenylmethyl.
 26. The compound of claim 24wherein R is hydrogen.
 27. The compound of claim 24,7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylicacid.
 28. The compound of claim 24, 7β-[[L-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylicacid.
 29. The compound of claim 24 wherein R is sodium.
 30. The compoundof claim 29, 7β-[[D-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0. [oct-2-ene-2-carboxylicacid, sodium salt.
 31. The compound of claim 29,7β-[[L-[[(2-propenylamino)carbonyl]amino]-2-thienylacetyl]amino]-3-[[(1methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylicacid, sodium salt.
 32. The compound of claim 22 wherein R₂ is --CH=CH₂.33. The compound of claim 32 wherein R is hydrogen.
 34. The compound ofclaim 32 wherein R is sodium.
 35. The compound of claim 22 wherein R₄ isphenyl.